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Monday, June 2, 2014

The GalNAc Wars

‘All
roads lead to GalNAc’ was the thoughtful, almost philosophical response by Alnylam’s CEO John
Maraganore when asked about the
GalNAc-conjugate challenge mounted by ISIS Pharmaceuticals for gene silencing in
hepatocytes.

With 20mg
per week (corresponding to less than 0.1mg/kg per week) and a much improved hepatocyte-specific
biodistribution of otherwise more promiscuous phosphorothioate chemistry,
GalNAc-antisense has suddenly re-emerged as a significant competitive threat to the
hepatocyte-targeted RNAi delivery solutions by Alnylam, Arrowhead Research, and
potentially other undisclosed efforts.
By comparison, 1st gen GalNAc-based ALN-TTRsc by Alnylam required at
least 10x more oligonucleotides to effect potent gene silencing in a phase Istudy in TTR amyloidosis.

2nd
gen ESC GalNAc-conjugates are claimed to be significantly more potent, but I
suspect that they won’t be that much more potent than GalNAc-ASOs and will have to win
the GalNAc battle based on safety.
Arrowhead’s GalNAc-targeted single-molecule DPCs should still be the most
potent of the bunch, but it is about time for them to advance them into the clinic as the
first-in-class train is leaving the station for an increased number of targets
and it is feeling the most-potent-in-class heat in its lead HBV indication that
is based on 2-molecule DPC.

With
GalNAcs applied in such a ubiquitous manner, you’d think that the likes of
Alnylam and ISIS Pharmaceuticals, not known for sitting on their hands when it comes to claiming ownership over technologies would start flexing their IP muscles. As I noted in a post from AsiaTIDES earlier
this year, the word on the lab floors is that GalNAcs per se are an old,
non-patentable free-for-all such that the IP focus should shift to other
aspects of the GalNAc-targeting approach such as linker
chemistries and economical manufacturing methods.

As much as
it is an interesting twist that ISIS would adopt Alnylam technology to become
competitive again for liver-directed gene silencing, the IP situation is
intriguing given the cross-licensing relationship between the two companies. The original arrangement going back to over a decade ago gave Alnylam access to IP from ISIS for the use in double-stranded
oligonucleotide therapeutics, and in return ISIS got access to IP from Alnylam for use in
single-stranded oligonucleotide therapeutics.
Whether this IP exchange includes IP that does not directly impinge on
oligonucleotide chemistry, such as aspects of delivery will be a critical element
in how easily an outright IP war could be triggered.

If Regulus
Therapeutics which has rights to Alnylam’s GalNAcs as evidenced by its
anti-miR122 candidate is a guide, the IP exchange would be broader than just
oligonucleotide chemistry. On the other
hand, I would be very surprised if strategy- and IP-savvy Alnylam did not foresee the
potential perils of also giving ISIS access to its delivery technologies.

In any
case, after the first verbal skirmishes, expect the saber-rattling around
GalNAc to increase with IP adding a new dimension to what has largely been a
battle based on potency and safety considerations.

Dirk, there is no IP conflict here. GalNAc as a delivery enhancer predates Alnylam or Isis. The earliest commercial GalNAc IP for oligos was patented by Alnylam's Mano Manoharan...while he was at Isis. Both Isis and Alnylam (and Regulus, and Santaris) have freedom to operate. Any IP revolves around the method for linking the GalNAc to the oligo, but the methods for doing this are virtually limitless. In the end, the "GalNAc wars" will be a wash, and we will be back to who has the best oligo for the best target.

I believe we are on the same page regarding GalNAc per se: a free-for-all. However, even Regulus referred to their Alnylam license when it disclosed it was using GalNAc for its miR122 program. Why mention it and pay license fees when it does not have to?

I'm pretty sure that while the exact realization can well be chemically unique in each case, the fundamental strategies can still be grouped into different buckets which may be patentable as a whole (e.g. protease- and/or lipase-sensitive linkers). Importantly, I have not been aware of a vigorous research effort around GalNAcs for oligo delivery until the last few years which should make it more likely that these buckets will not be considered obvious by the patent offices.

Too much is at stake, and Alnylam would want to prevent everybody and their brothers join the party on equal footing.

One question I have, though, is that if GalNAc conjugation has been known for so long and is apparently pretty effective, why hasn't Isis gotten it work before now? They've been around a lot longer than Alnylam. What's been the key to getting it to work now? Isn't that what we need to look at in terms of whether there's any IP there to protect?

Thanks for the Regulus clarification. I'm wondering though to what degree, if at all, Alnylam is assisting them to realize it.

Regarding ISIS and why they haven't employed GalNAc yet? Good question. I'm actually been wondering why they have not done too much in terms of adding chemistries to their oligos for enhancing delivery and making it more specific in general. It's an obvious opportunity to increase potency and safety. Cost or out of a sheer aesthetic sense that antisense should stay as simple as possible?

For those interested into the structure and synthesis of "Alnylam's" tridentate GalNAc ligand please have a look to this paper from dutch colleagues (from 1999): http://www.ncbi.nlm.nih.gov/pubmed/10052968Does someone knows an older paper and/or patent regarding this TRIS-based ligand? Alnylam's oligo coupling chemistry especially with respect to the solid phase synthesis is worth mentioning... V.

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